Project Summary: Compounds containing chiral centers that are remotely located from other functional groups are commonly found in biologically active compounds. However, the enantioselective synthesis of such chiral centers is challenging and, thus, developing new methods to streamline their access are in high demand. Therefore, we are targeting a new collection of alkene functionalization processes, which enable site and enantioselective addition reactions of relatively electronically unbiased multi-substituted alkenes. To accomplish this, we will exploit palladium catalysis through a unique mechanistic process in which, after initial addition of the Pd- organometallic species to the alkene, the catalyst migrates through an alkyl chain to ultimately oxidize a distant functional group. Therefore, this approach provides a comprehensive strategy to streamline the enantioselective synthesis of building blocks incorporating remote tertiary and quaternary chiral centers that are positioned at nearly any distance from the pendant preexisting functional group. The method development is coupled to careful mechanistic studies, which are designed to elucidate the fundamental features governing reaction outcomes, as well as to stimulate new reaction development and catalyst design. In this context, the current renewal application is focused on a) determining if other coupling partners besides aryl boronic acids can be used in a site and enantioselective manner including alkenyl (Aim 1) and alkyl groups (Aim 2) as well as direct coupling of electron-rich heteroaromatic systems (Aim 1), b) expanding the types of alkenes used to more challenging examples, including 1,1-disubstituted variants, which set a chiral center ? to the site of addition, and tetrasubstituted alkenes, which allow for the formation of vicinal chiral centers but have not been a competent substrate class in intermolecular Heck reactions (Aim 1), c) evaluating other functional groups remotely attached to the alkene, which allow for the formation of unique products as well as tests remote electronic effects on site selectivity (Aim 2), and d) pursuing the concept of setting multiple chiral centers at distant sites through alkene difunctionalization reactions (Aim 3).